Genome-Wide Search for Nonadditive Allele Effects Identifies PSKH2 as Involved in the Variability of Factor V Activity.

BACKGROUND: Factor V (FV) is a key molecular player in the coagulation cascade. FV plasma levels have been associated with several human diseases, including thrombosis, bleeding, and diabetic complications. So far, 2 genes have been robustly found through genome-wide association analyses to contribute to the inter-individual variability of plasma FV levels: structural F5 gene and PLXDC2. METHODS AND RESULTS: The authors used the underestimated Brown-Forsythe methodology implemented in the QuickTest software to search for non-additive genetic effects that could contribute to the inter-individual variability of FV plasma activity. QUICKTEST was applied to 4 independent genome-wide association studies studies (LURIC [Ludwigshafen RIsk and Cardiovascular Health Study], MARTHA [Marseille Thrombosis Association], MEGA [Multiple Environmental and Genetic Assessment], and RETROVE [Riesgo de Enfermedad Tromboembolica Venosa]) totaling 4505 participants of European ancestry with measured FV plasma levels. Results obtained in the 4 cohorts were meta-analyzed using a fixed-effect model. Additional analyses involved exploring haplotype and gene×gene interactions in downstream investigations. A genome-wide significant signal at the PSKH2 locus on chr8q21.3 with lead variant rs75463553 with no evidence for heterogeneity across cohorts was observed (P=0.518). Although rs75463553 did not show an association with mean FV levels (P=0.49), it demonstrated a robust significant (P=3.38x10-9) association with the variance of FV plasma levels. Further analyses confirmed the reported association of PSKH2 with neutrophil biology and revealed that rs75463553 likely interacts with two loci, GRIN2A and POM121L12, known for their involvement in smoking biology. CONCLUSIONS: This comprehensive approach identifies the role of PSKH2 as a novel molecular player in the genetic regulation of FV, shedding light on the contribution of neutrophils to FV biology.

Unraveling athletic performance: Transcriptomics and external load monitoring in handball competition.

OBJECTIVE: This study aims to comprehend the impact of handball practice on sub-elite athletes by investigating transcriptomic changes that occur during a match. The primary focus encompasses a dual objective: firstly, to identify and characterize these transcriptomic alterations, and secondly, to establish correlations between internal factors (gene expression), and external loads measured through Electronic Performance and Tracking Systems (EPTS variables). Ultimately, this comprehensive analysis seeks to evaluate both acute and chronic responses to exercise within the context of handball training. METHODS: The study included sixteen elite male athletes from the FC Barcelona handball second team. Blood samples were extracted at three different time points: before the match at baseline levels (T1), immediately upon completion (T2), and 24 hours after completion (T3). Differential gene expression, Gene Ontology Term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted in two comparisons: Comparison 1 (T1 vs T2) and Comparison 2 (T1 vs T3). Further, the correlation between gene expression levels and training variables (external load) was conducted. RESULTS: In T1 vs T2, 3717 of the 14632 genes detected were differentially expressed (adjusted p-value < 0.05), and enrichment of terms related to the immune system, mitochondria, and metabolic processes was found. Further, significant linear correlations were obtained between High-Speed running (HSR) and high-intensity variables such as acceleration ACC and deceleration DEC values with amino acids, and inflammatory and oxidative environment-related pathways, both in chronic and acute response. CONCLUSIONS: This research highlights the effects of external workload on elite athletes during a handball match and throughout the season. The study identifies deregulation in the immune system, mitochondrial functions, and various metabolic pathways during the match. Additionally, it establishes correlations between the external load and pathways associated with amino acids, inflammation, oxidative environment, and regulation. These findings offer insights into the immediate and chronic responses of athletes to physical effort.

Cost-effectiveness of apixaban and rivaroxaban in thromboprophylaxis of cancer patients treated with chemotherapy in Spain.

BACKGROUND: Apixaban and rivaroxaban are two direct-acting oral anticoagulants (DOACs) recommended for thromboprophylaxis in cancer patients treated with chemotherapy in an ambulatory setting. We aimed to assess the cost-utility of thromboprophylaxis with apixaban and rivaroxaban vs no thromboprophylaxis in ambulatory cancer patients starting chemotherapy with an intermediate-to-high risk of venous thromboembolism (VTE), Khorana score ≥ 2 points. METHODS: A cost-effectiveness analysis was performed from the perspective of Spain's National Health System (NHS) using an analytical decision model in the short-term (180 days) and a Markov model in the long-term (5 years). Transition probabilities were obtained from randomized, double-blind, placebo-controlled clinical trials of apixaban and rivaroxaban in adult ambulatory patients with cancer at risk for VTE, treated with chemotherapy (AVERT and CASSINI trials). The costs (€2,021) were taken from Spanish sources. The utilities of the model were obtained through the EQ-5D questionnaire. Deterministic (base case) and probabilistic (second-order Monte Carlo simulation) analyses were conducted. RESULTS: In the probabilistic sensitivity analysis, apixaban generated a cost per patient of €1,082 ± 187, with a 95% confidence interval (CI) of €713-1,442, while no prophylaxis produced a cost per patient of €1,146 ± 218, with a 95% CI of €700-1,491, with a saving of €64 per patient and a gain of 0.008 QALYs. Likewise, rivaroxaban provided a cost per patient of €993 ± 133, with a 95% CI of €748-1,310, while no prophylaxis produced a cost per patient of €872 ± 152, with a 95% CI of €602-1,250, with an additional expense of €121 per patient and a gain of 0.008 QALYs. CONCLUSIONS: In thromboprophylaxis of cancer patients, the use of apixaban and rivaroxaban generated similar costs compared to non-prophylaxis, without the difference found being statistically significant, with a clinically insignificant QALY gain.

Polygenic risk of major depressive disorder as a risk factor for venous thromboembolism.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are associated with an increased risk of cardiovascular diseases, including venous thromboembolism (VTE). The reasons for this are complex and include obesity, smoking, and use of hormones and psychotropic medications. Genetic studies have increasingly provided evidence of the shared genetic risk of psychiatric and cardiometabolic illnesses. This study aimed to determine whether a genetic predisposition to MDD, BD, or SCZ is associated with an increased risk of VTE. Genetic correlations using the largest genome-wide genetic meta-analyses summary statistics for MDD, BD, and SCZ (Psychiatric Genetics Consortium) and a recent genome-wide genetic meta-analysis of VTE (INVENT Consortium) demonstrated a positive association between VTE and MDD but not BD or SCZ. The same summary statistics were used to construct polygenic risk scores for MDD, BD, and SCZ in UK Biobank participants of self-reported White British ancestry. These were assessed for impact on self-reported VTE risk (10 786 cases, 285 124 controls), using logistic regression, in sex-specific and sex-combined analyses. We identified significant positive associations between polygenic risk for MDD and the risk of VTE in men, women, and sex-combined analyses, independent of the known risk factors. Secondary analyses demonstrated that this association was not driven by those with lifetime experience of mental illness. Meta-analyses of individual data from 6 additional independent cohorts replicated the sex-combined association. This report provides evidence for shared biological mechanisms leading to MDD and VTE and suggests that, in the absence of genetic data, a family history of MDD might be considered when assessing the risk of VTE.

Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels.

BACKGROUND: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. METHODS: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. RESULTS: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. CONCLUSIONS: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.

A Clinical-Genetic Risk Score for Predicting Cancer-Associated Venous Thromboembolism: A Development and Validation Study Involving Two Independent Prospective Cohorts.

PURPOSE: Venous thromboembolism (VTE) is a leading cause of death among patients with cancer. The Khorana score was developed for assessing the risk of VTE in outpatients with cancer receiving chemotherapy, but its accuracy in identifying patients at high risk has been questioned. The aim of this study was to develop and validate a clinical-genetic score that improves the assessment of VTE risk in oncology outpatients within 6 months of diagnosis. METHODS: The new score was developed using the data of 364 outpatients belonging to the Spanish ONCOTHROMB 12-01 population. In this cohort, clinical data associated with the risk of VTE were collected at the time of diagnosis, including the Khorana score. These patients were also genotyped for the 51 genetic variants known to be associated with VTE. Multivariate logistic regression was performed to determine the weight of each genetic and clinical variable in relation to VTE risk, allowing a clinical-genetic risk score (the ONCOTHROMB score) to be developed. The Khorana and the ONCOTHROMB scores were then compared via the area under the receiver operating characteristic curve (AUC), calibration, and the number of patients needed to treat. The new score was then validated in a study of 263 patients in the Vienna Cancer and Thrombosis Study population. RESULTS: Nine genetic variants, tumor site, TNM stage, and a body mass index of > 25 kg/m2 were found to be associated with VTE and were used to build the ONCOTHROMB score, which better predicted the overall risk of VTE than did the Khorana score (AUC, 0.781 v 0.580; P < .001). Similar AUC results were recorded in the validation study the Vienna Cancer and Thrombosis Study cohort involving patients with the same type of tumor (AUC for the ONCOTHROMB score v the Khorana score: 0.686 v 0.577; P < .001) and with all type of tumors (AUC for the ONCOTHROMB score v the Khorana score: 0.720 v 0.561; P < .0001). CONCLUSION: The ONCOTHROMB score for VTE risk in outpatients with cancer, which takes into account both clinical and genetic variables, better identifies patients who might benefit from primary thromboprophylaxis than does the Khorana score.

Multiallelic Copy Number Variation in ORM1 is Associated with Plasma Cell-Free DNA Levels as an Intermediate Phenotype for Venous Thromboembolism.

Venous thromboembolism (VTE) is a common disease with high heritability. However, only a small portion of the genetic variance of VTE can be explained by known genetic risk factors. Neutrophil extracellular traps (NETs) have been associated with prothrombotic activity. Therefore, the genetic basis of NETs could reveal novel risk factors for VTE. A recent genome-wide association study of plasma cell-free DNA (cfDNA) levels in the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT-2) Project showed a significant associated locus near ORM1. We aimed to further explore this candidate region by next-generation sequencing, copy number variation (CNV) quantification, and expression analysis using an extreme phenotype sampling design involving 80 individuals from the GAIT-2 Project. The RETROVE study with 400 VTE cases and 400 controls was used to replicate the results. A total of 105 genetic variants and a multiallelic CNV (mCNV) spanning ORM1 were identified in GAIT-2. Of these, 17 independent common variants, a region of 22 rare variants, and the mCNV were significantly associated with cfDNA levels. In addition, eight of these common variants and the mCNV influenced ORM1 expression. The association of the mCNV and cfDNA levels was replicated in RETROVE (p-value = 1.19 × 10-6). Additional associations between the mCNV and thrombin generation parameters were identified. Our results reveal that increased mCNV dosages in ORM1 decreased gene expression and upregulated cfDNA levels. Therefore, the mCNV in ORM1 appears to be a novel marker for cfDNA levels, which could contribute to VTE risk.

TMAO and Gut Microbial-Derived Metabolites TML and γBB Are Not Associated with Thrombotic Risk in Patients with Venous Thromboembolism.

BACKGROUND: The present work evaluates the association between circulating concentrations of Trimethylamine-N-oxide (TMAO), gamma butyrobetaine (γBB), and trimetyllisine (TML) in controls and patients with venous thromboembolism (VTE) with coagulation parameters. METHODS: The study involved 54 VTE patients and 57 controls. Platelet function, platelet hyperreactivity, platelet adhesiveness, thrombosis-associated parameters, and thrombin generation parameters were studied. Plasma TMAO, γBB, and TML determination was performed using an ultra-high-performance liquid chromatography system coupled with mass spectrometry. RESULTS: No differences were found for TMAO, γBB, or TML concentrations between controls and VTE patients. In thrombin generation tests, TMAO, γBB, and TML showed a positive correlation with lag time and time to peak. TMAO, γBB, and TML negatively correlated with peak height. No significant differences were observed regarding TMAO, γBB, and TML concentrations between the two blood withdrawals, nor when the control and VTE patients were analyzed separately. No correlation was observed between these gut metabolites and platelet function parameters. CONCLUSIONS: No differences were found regarding TMAO, γBB, and TML concentrations between the control and VTE groups. Some correlations were found; however, they were mild or went in the opposite direction of what would be expected if TMAO and its derivatives were related to VTE risk.

Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk.

Plasma cell-free DNA (cfDNA) is a surrogate marker of neutrophil extracellular traps (NETs) that contribute to immunothrombosis. There is growing interest about the mechanisms underlying NET formation and elevated cfDNA, but little is known about the factors involved. We aimed to identify genes involved in the regulation of cfDNA levels using data from the Genetic Analysis of Idiopathic Thrombophilia (GAIT-2) Project.Imputed genotypes, whole blood RNA-Seq data, and plasma cfDNA quantification were available for 935 of the GAIT-2 participants from 35 families with idiopathic thrombophilia. We performed heritability and GWAS analysis for cfDNA. The heritability of cfDNA was 0.26 (p = 3.7 × 10-6), while the GWAS identified a significant association (rs1687391, p = 3.55 × 10-10) near the ORM1 gene, on chromosome 9. An eQTL (expression quantitative trait loci) analysis revealed a significant association between the lead GWAS variant and the expression of ORM1 in whole blood (p = 6.14 × 10-9). Additionally, ORM1 expression correlated with levels of cfDNA (p = 4.38 × 10-4). Finally, genetic correlation analysis between cfDNA and thrombosis identified a suggestive association (ρ g = 0.43, p = 0.089).All in all, we show evidence of the role of ORM1 in regulating cfDNA levels in plasma, which might contribute to the susceptibility to thrombosis through mechanisms of immunothrombosis.

Impact of pre-admission antithrombotic therapy on disease severity and mortality in patients hospitalized for COVID-19.

Anticoagulant therapy is a cornerstone treatment for coronavirus disease 2019 (COVID-19) due to the high rates of thromboembolic complications associated with this disease. We hypothesized that chronic antithrombotic therapy could play a protective role in patients hospitalized for COVID-19. Retrospective, observational study of all patients admitted to our hospital for ≥ 24 h from March 1 to May 31, 2020 with SARS-CoV-2. The objective was to evaluate clinical outcomes and mortality in COVID-19 patients receiving chronic anticoagulation (AC) or antiplatelet therapy (AP) prior to hospital admission. A total of 1612 patients were evaluated. The mean (standard deviation; SD) age was 66.5 (17.1) years. Patients were divided into three groups according to the use of antithrombotic therapy prior to admission (AP, AC, or no-antithrombotic treatment). At admission, 9.6% of the patients were taking anticoagulants and 19.1% antiplatelet therapy. The overall mortality rate was 19.3%. On the multivariate analysis there were no significant differences in mortality between the antithrombotic groups (AC or AP) and the no-antithrombotic group (control group). Patients on AC had lower ICU admission rates than the control group (OR: 0.41, 95% CI, 0.18-0.93). Anticoagulation therapy prior to hospitalization for COVID-19 was associated with lower ICU admission rates. However, there were no significant differences in mortality between the patients receiving chronic antithrombotic therapy and patients not taking antithrombotic medications. These findings suggest that chronic anticoagulation therapy at the time of COVID-19 infection may reduce disease severity and thus the need for ICU admission.

Incorporating genetic and clinical data into the prediction of thromboembolism risk in patients with lymphoma.

BACKGROUND: The incorporation of genetic variables into risk scores for predicting venous thromboembolic events (VTE) could improve their capacity to identify those patients for whom thromboprophylaxis would be most beneficial. Proof-of-concept of this is provided by the TiC-ONCO score for predicting the risk of VTE in patients with solid tumours. Our aim was to develop a similarly improved tool-the TiC-LYMPHO score-for predicting VTE in patients with lymphoma. METHODS: In a retrospective observational study of 208 patients with lymphoma, 31 (14.9%) were found to have experienced an episode of VTE either at the time of diagnosis or over the next 6 months. Clinical variables associated with VTE, determined via logistic regression analysis, plus the same genetic variables included in the TiC-ONCO score, were used to build the TiC-LYMPHO score algorithm. The sensitivity, specificity, predictive values and AUC of the TiC-LYMPHO, the Khorana and ThroLy scores were compared in the same population. RESULTS: The TiC-LYMPHO score showed a significantly higher AUC, sensitivity and NPV (0.783, 95.35% and 97.98% respectively) than the other scores. The ThroLy score showed a significantly higher specificity (96.43% vs. 54.49%; p < 0.0001) and PPV (37.50% vs. 26.36%; p = 0.0147) than the TiC-LYMPHO score, whereas its AUC, sensitivity and NPV were significantly lower (0.579, 19.35% and 86.48%, respectively). CONCLUSION: These results show that by incorporating genetic and clinical data into VTE risk assessment, the TiC-LYMPHO score can categorize patients with lymphoma better in terms of their risk of VTE and allow individualized thromboprophylaxis to be prescribed.

Predictive Ability of a Clinical-Genetic Risk Score for Venous Thromboembolism in Northern and Southern European Populations.

Venous thromboembolism (VTE) is a complex, multifactorial problem, the development of which depends on a combination of genetic and acqfiguired risk factors. In a Spanish population, the Thrombo inCode score (or TiC score), which combines clinical and genetic risk components, was recently proven better at determining the risk of VTE than the commonly used model involving the analysis of two genetic variants associated with thrombophilia: the Factor V Leiden (F5 rs6025) and the G20210A prothrombin (F2 rs1799963). The aim of the present case-control study was to validate the VTE risk predictive capacity of the TiC score in a Northern European population (from Sweden). The study included 173 subjects with VTE and 196 controls. All were analyzed for the genetic risk variants included in the TiC gene panel. Standard measures -receiver operating characteristic (ROC) area under the curve (AUC), sensitivity, specificity, and odds ratio (OR)-were calculated. The TiC score returned an AUC value of 0.673, a sensitivity of 72.25%, a specificity of 60.62%, and an OR of 4.11. These AUC, sensitivity, and OR values are all greater than those associated with the currently used combination of genetic variants. A TiC version adjusted for the allelic frequencies of the Swedish population significantly improved its AUC value (0.783). In summary, the TiC score returned more reliable risk estimates for the studied Northern European population than did the analysis of the Factor V Leiden and the G20210A genetic variations in combination. Thus, the TiC score can be reliably used with European populations, despite differences in allelic frequencies.

Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation.

Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, âˆ¼1.2), the A1 and B haplotypes are associated with an âˆ¼1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, âˆ¼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.

The impact of sex on gene expression across human tissues.

Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.

Cell type-specific genetic regulation of gene expression across human tissues.

The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped interactions between computational estimates of cell type abundance and genotype to identify cell type-interaction QTLs for seven cell types and show that cell type-interaction expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 87 complex traits show a contribution from cell type-interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue.

Expression of microRNAs in human platelet-poor plasma: analysis of the factors affecting their expression and association with proximal genetic variants.

To translate circulating microRNAs (miRNAs) into the clinic, a deeper understanding of the factors affecting their expression is needed. In this study, we explored the features affecting the expression of miRNAs and their genetic regulation using the expression data of 103 miRNAs obtained by qPCR in the platelet-poor plasma of 104 subjects. The principal components (PCs) of the expression of the miRNAs were associated with technical and biological features (e.g., synthetic controls or sex) and with blood cell counts. Also, the associations with proximal genetics variants were analysed. We found that haemolysis marker (dCt hsa-miR-23a-3p-hsa-miR-451a) was correlated strongly (ß = 0.84, p = 2.07x10-29) with the second PC, which explained 10.1% of the overall variability. Thus, we identified haemolysis as a source of variability for miRNA expression even in mild hemolyzed samples (haemolysis marker dCt <5). In addition to hsa-miR-23a-3p and hsa-miR-451a, the miRNAs most stable and most susceptible to haemolysis were identified. Then, we discovered that the expression of miRNAs in platelet-poor plasma was not biased by any blood cell count, and thus, our results supported their role as biomarkers of tissue-specific conditions. Finally, we identified 1,323 genetic variants that corresponded to 158 miRNA expression quantitative trait loci for 14 miRNAs (FDR <0.2), which were enriched in promoter regions (p = 0.03). This enrichment corresponded to a range of specific tissues (e.g., breast or fat) although not to blood tissue, supporting the concept that the expression of circulating miRNAs is under the genetic control of different tissues.

The TAGA Study: A Study of Factors Determining Aortic Diameter in Families at High Risk of Abdominal Aortic Aneurysm Reveal Two New Candidate Genes.

A variety of disorders are known to be related with aortic geometry, among them abdominal aortic aneurysm (AAA). This work aims to present the main determinants of abdominal aortic diameter in a new cohort of families at high risk of AAA. The Triple-A Genomic Analysis (TAGA) study comprises 407 individuals related in 12 families. Each family was collected through a proband with AAA. We calculated heritability and genetic correlations between abdominal aortic diameter and clinical parameters. A genome-wide linkage scan was performed based on 4.6 million variants. A predictive model was calculated with conditional forest. Heritability of the abdominal aortic diameter was 34%. Old age, male sex, higher height, weight, creatinine levels in serum, and better lung capacity were the best predictors of aortic diameter. Linkage analyses suggested the implication of Epidermal Growth Factor Receptor (EGFR) and Betacellulin (BTC) genes with aortic diameter. This is the first study to evaluate genetic components of variation of the aortic diameter in a population of AAA high-risk individuals. These results reveal EGFR, a gene that had been previously implicated in AAA, as a determinant of aortic diameter variation in healthy genetically enriched individuals, and might indicate that a common genetic background could determine the diameter of the aorta and future risk of AAA.

Identification of a Plasma MicroRNA Profile Associated With Venous Thrombosis.

OBJECTIVE: Venous thrombosis (VT) is a complex condition with a highly heritable genetic component that predisposes one to its development. Certain microRNAs (miRNAs) might be used as biomarkers of VT, but few studies have examined miRNA expression in this respect. The aim of the present work was to identify a plasma miRNA profile associated with VT. Approach and Results: miRNAs were analyzed by quantitative polymerase chain reaction in plasma samples from members of the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia 2) population (n=935). A discovery phase involving the screening of 752 miRNAs from a subset of 104 GAIT-2 subjects was followed by an internal validation phase in which the selected miRNAs were quantified in the whole GAIT-2 population. In the discovery phase, 16 miRNAs were selected, including 9 associated with VT and 7 that correlated with an intermediate phenotype of VT. In the next phase, 4 miRNAs were validated as differentially expressed (false discovery rate, <0.1) in VT: hsa-miR-126-3p, hsa-miR-885-5p, hsa-miR-194-5p, and hsa-miR-192-5p. The 4 miRNAs each returned a significant (P<0.05) odds ratio for VT (range of 1.3-1.8). A risk model including the 4 miRNAs, age, and sex returned an area under the receiver operating characteristic curve of 0.77. Moreover, all 4 miRNAs showed significant correlations with intermediate phenotypes of VT (eg, protein S and factor VII). The targets of the miRNAs in the blood coagulation pathway and their interactions are also discussed. CONCLUSIONS: The present results suggest a 4-miRNA plasma profile associated with VT is of potential use in predicting the risk of this condition.